Retrospective Case Series Analysis of RAF Family Alterations in Pancreatic Cancer: Real-World Outcomes From Targeted and Standard Therapies

PURPOSE In pancreatic cancer (PC), the RAF family alterations define a rare subset of patients that may predict response to inhibition of the BRAF/MEK/ERK signaling pathway. A comprehensive understanding of the molecular and clinical characteristics of RAF-mutated PC may support future development of RAF-directed strategies. METHODS Clinical outcomes were assessed across a multi-institutional case series of 81 patients with RAF family-mutated PC. Mutational subgroups were defined on the basis of RAF alteration hotspots and therapeutic implications. RESULTS The frequency of RAF alterations in PC was 2.2% (84 of 3,781) within a prevalence cohort derived from large molecular databases where BRAF V600E (Exon 15), BRAF Delta NVTAP (Exon 11), and SND1-BRAFfusions were the most common variants. In our retrospective case series, we identified 17 of 81 (21.0%) molecular profiles with a BRAF V600/Exon 15 mutation without any confounding drivers, 25 of 81 (30.9%) with BRAF or RAF1 fusions, and 18 of 81 (22.2%) with Exon 11 mutations. The remaining 21 of 81 (25.9%) profiles had atypical RAF variants and/or multiple oncogenic drivers. Clinical benefit from BRAF/MEK/ERK inhibitors was observed in 3 of 3 subjects within the V600 subgroup (two partial responses), 4 of 6 with fusions (two partial responses), 2 of 6 with Exon 11 mutations (one partial response), and 0 of 3 with confounding drivers. Outcomes analyses also suggested a trend favoring fluorouracil-based regimens over gemcitabine/nab-paclitaxel within the fusion subgroup (P = .027). CONCLUSION Prospective evaluation of RAF-directed therapies is warranted in RAF-mutated PC; however, differential responses to targeted agents or standard regimens for each mutational subgroup should be a consideration when designing clinical trials. (C) 2021 by American Society of Clinical Oncology

Automated summary

In pancreatic cancer patients with RAF family alterations, different mutational subgroups were identified and their clinical characteristics were determined, which may contribute to the development of future treatment strategies.